Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL) diagnosed in the United States, accounting for over 20,000 new cases annually. DLBCL is an aggressive tumor and, despite a high response rate to initial therapy, approximately 40% of patients will ultimately die from their lymphoma. Treatment of DLBCL would benefit greatly from the advent of early diagnostics and new therapeutics. The emerging field of epigenomics is expected to provide such opportunities for most diseases, including DLBCL. The epigenome consists of covalent marks placed on the DNA and histone components of chromatin, which form distinct patterns to regulate gene expression. Changes in normal epigenetic patterns lead to inappropriate gene activation or silencing, which has been linked to numerous pathologies. For example, cancer cells silence tumor suppressor genes by revising the pattern of chromatin modifications near transcriptional promoters. In contrast to the immutability of disease-causing genetic lesions, epigenetic modifications are reversible, offering the possibility of new therapeutic modalities. Despite recent progress, the vast majority of epigenetic changes that characterize human disease, including DLBCL, and their underlying mechanisms remain unknown. We hypothesize that that the epigenome of DLBCL tumors from different patients will harbor common signatures that can be used as reporters for the disease and provide insights into mechanisms of gene regulation that promote lymphomagenesis. A subset of these signatures likely corresponds to new control elements that coordinate the aberrant expression of gene cohorts in DLBCL tumors (Intergenic Tumor-specific Control Hubs;ITCHs). We now propose a transformational research plan relying on established collaborations between basic and clinical scientists to (i) compare the epigenomes of primary DLBCL tumors with matched circulating B cells from each patient, (ii) identify ITCHs that govern the inappropriate expression of certain DLBCL gene cohorts, and (iii) innovate a therapeutic approach called Focused Epigenetic Therapy of Control Hubs (FETCH), in which ITCHs are specifically targeted for reversal of their abnormal epigenetic landscape with consequential restoration of normal expression at their gene cohorts. Together, these studies will not only provide a foundational dataset for gauging the feasibility of epigenomic approaches to NHL and other cancers, but will also guide future efforts to develop precision epigenetic therapies for reversing aberrant gene expression patterns that characterize a wide range of human diseases. PUBLIC HEALTH RELEVANCE: The packaging of DNA in the nucleus is a key determinant of gene function;changes in these "epigenetic" programs are likely to be at the heart of many diseases. We propose studies to characterize the epigenome of lymphocytes in patients suffering from a common form of non-Hodgkin Lymphoma, with the goal of establishing tumor-specific epigenetic signatures. The signatures will then be targeted for a novel therapy in which abnormal epigenetic patterns are reversed specifically at regions in the genome that control the inappropriate expression of lymphoma genes.